Type 1 diabetes (T1D) is a common autoimmune disease that causes destruction of
pancreatic, insulin producing beta cells, leading to high blood glucose. T1D is regarded
as a childhood disease with an average age of diagnosis of 13 years, but the age
presentation is very variable from young infants until late adulthood.
In Exeter, a group of rare children who have developed T1D in the first year of life
(Patel) is described as having Extremely Early-onset Type 1 Diabetes (EET1D). Studying
these rare patients is important because they are presenting with autoimmunity at the
beginning of life when the immune system is not yet fully developed and at a time when
pancreatic autoimmunity first emerges (Krisher), so this study may give novel insights
into the cause of T1D.
The Exeter Molecular Genetics Laboratory is a world referral centre
(www.diabetesgenes.org) for Neonatal Diabetes (NDM). Most cases of diabetes diagnosed
under 6 months do not have EET1D but have genetic mutations in beta cell genes that lead
to impaired insulin production (NDM)(Ellard; De Franco). Exeter is able to identify the
remaining <20% without a mutation in a beta cell gene who actually have EET1D. Exeter
uses a novel measure of T1D risk genes, called the T1D Genetic Risk Score (T1D GRS),
showing that a proportion of the remaining patients have very high T1D risk and therefore
EET1D(Patel). Understanding the mechanism for very early presentation could be highly
important as immune strategies to intervene before or after people get T1D may differ by
age of onset.
The results may focus the research community on events that occur before birth and may
then inform new efforts to prevent or intervene in the underlying destruction of beta
cells in T1D.
Additional funding extended the study to include recruitment of infants without diabetes,
aged 0-6 years, as controls to enable assessment of how the abnormalities found in
autoimmune and non-autoimmune diabetes compare to normal early life development of the
immune system.
Hypotheses:
i) Extreme early-onset T1D (EET1D) is associated with classic biomarkers of T1D, such as
islet specific autoantibodies, autoreactive islet specific CD8 T cells, and loss of beta
cell function, whereas children with monogenic neonatal diabetes or without diabetes will
not show abnormalities in these markers.
ii) EET1D will be associated with more rapid beta cell loss than T1D presenting at older
ages.
iii) The mechanisms for EET1D will be due to rare changes in immune genes or due to a
particularly potent, early response of the immune system to beta cells, as measured by
autoreactive T cells or immune gene expression when compared to older onset T1D.
Study Aim: The EXE-T1D study will take people with T1D diagnosed before the age of 24
months and compare them to people with T1D diagnosed at more typical ages (1-20 years)
and people diagnosed with non-autoimmune diabetes at a similar very young age (children
with neonatal diabetes [NDM]), and infants without diabetes matched for age.
EXE-T1D is an observational study organised into two sub-studies:
Study 1: Cross-sectional study of existing patients with EET1D (n=100 v 100): Assess
islet autoantibodies, islet T cell autoimmunity, C-peptide, RNAseq, genetics and clinical
features of EET1D compared to T1D in selected patients of varying ages and durations of
diabetes referred over the last 15 years to the Exeter genetics team/Prof Oram.
Study 2: Newly referred patients (n=20 v 20): Recruit newly diagnosed patients with EET1D
who are referred to Exeter/Prof Oram for diagnostic testing to allow assessment of immune
phenotype in patients close to diagnosis(Abreu; Unger; Velthuis). Assess immune function
longitudinally by collecting a blood sample for serum and peripheral lymphocytes, islet
autoantibodies and C-peptide assessment shortly after referral, and approximately 2 years
later.
The investigators may also be approached by patients' GPs and by patients themselves.
Recruitment to the study in this setting will be by the investigator's team who will
provide information about the study and feedback inclusion of the participant in the
study to the GP and diabetes clinician as appropriate.
UK participants will be recruited under UK wide ethics. Exeter will recruit patients from
international centres in collaboration with local clinicians that have specific
Institutional Review Board (IRB) approval.
The Exeter Clinical Laboratories encompass the Exeter Blood Sciences Laboratory and
Exeter Molecular Genetics Laboratory at the Royal Devon and Exeter NHS Foundation Trust
and will perform C-peptide, islet autoantibody and genetic tests.
Peripheral lymphocyte (PBMC) analysis for autoreactive CD4 and CD8 T cells will be
performed by Tim Tree (King's College London). RNAseq will be performed by Cate Speake
and the Benaroya Research Institute, Seattle (USA).
All participants (or their legal guardian) recruited to the study will be required to
give written informed consent and will be informed of their right to withdraw from the
study at any time without prejudice or jeopardy to any future clinical care.
Patients identified and screened as being suitable for this study will have a blood
sample and optional urine sample collected by the clinical team at a time and location
suitable for the patient, clinical and study teams.
Study 2: In addition to the first visit, a repeat blood sample for PBMC, C-peptide and
Autoantibody analysis may be collected, approximately 2 years (+/-6 months) later.
Non-UK samples will be collected by collaborating international centres with their own
IRB approval. The local team will spin and freeze the EDTA plasma sample and store it on
site while the PBMCs are extracted as per Exeter's SOP. All tubes will then be couriered
to Exeter. If no local team is available to extract PBMCs, all tubes will be couriered to
Exeter for analysis. For some centres, it may be possible to arrange for the samples to
be flown directly to the UK for PBMC extraction.
End of Study Definition: last participant's final study visit plus 6 months to enable
follow-up data capture.
Safety, Definitions and Reporting Risks Blood samples will be collected by staff trained
in venepuncture. Any potential discomfort or side-effects will be equivalent to that
experienced in routine clinical care.
Benefits The C-peptide and autoantibody results may help to confirm a diagnosis of T1D so
will be reported back to clinicians responsible for the patient's diabetes care.
Decisions about ongoing clinical care and treatment will be made externally to the
research study but treatment will be recorded.
Adverse effects Should any unforeseen adverse events arise that are possibly, probably,
or definitely related to a study procedure, they will be reported to the Sponsor and
CI/central coordinating team within 24 hours of the CI or PI or co-investigators becoming
aware of the event.
Confidentiality All information related to study participants will be kept confidential
and managed in accordance with the Data Protection Act, NHS Caldicott Guardian, The
Research Governance Framework for Health and Social Care and Research Ethics Committee
Approval.
Participant data will be held in a link-anonymised format, with personal identifiable
data only accessible to personnel with training in data protection who require this
information to perform their study role.
Record Retention and Archiving When the research study is complete, it is a requirement
of the Research Governance Framework and Sponsor Trust Policy that the records are kept
for a further 15 years.
Local investigator site files must be archived at the external site according to local
R&D requirements. They will not be stored at the coordinating centre's archiving
facility.
Statistical Considerations Sample Size Total recruitment target is at least 240: Study 1:
100 with EET1D plus 100 controls (N=200); Study 2: EET1D v Monogenic / NDM controls
(N=30+); Non-diabetic controls: (N=20+) Feasibility: The sample size has been selected to
assess feasibility rather than on the basis of statistical power. In reality with these
extremely rare but potentially very interesting patients, every single patient recruited
could contribute on their own to a novel discovery. The immune, beta cell or autoantibody
differences the study may reveal are unknown but a group of 20 v 20 gives an 80% power
(alpha 0.05) to detect a difference of 10% v 50% in a proportion between the two groups
and a power of 85% (alpha 0.05) to detect a 1 SD difference in a continuous variable.
Statistical analysis: The EET1D as described are unique and findings in the various
studies are difficult to predict given the novel nature of this study. The study using
100 EET1D v 100 controls gives a 90% power (alpha 0.05) to detect a difference in
proportions of a binary variable of 50% v 30% and a 0.6SD difference in a continuous
variable, and similarly a group of 20 v 20 gives an 80% power (alpha 0.05) to detect a
difference of 10% v 50% in the two groups and a power of 85% (alpha 0.05) to detect a 1
SD difference in a continuous variable.
Monitoring ensure compliance with Good Clinical Practice. The Investigators will permit
monitoring, audits, REC review, and regulatory inspections by providing the Sponsor(s),
Regulators and REC direct access to source data and other documents.
No financial and other competing interests to disclose for the Chief Investigator, PIs at
each site and committee members for the overall study management.
NHS Indemnity will apply to UK participants and UK public liability insurance is provided
by the University of Exeter.
Accidental protocol deviations must be adequately documented and reported to the Chief
Investigator and Sponsor immediately.
Access to the final study dataset The Exeter study team will have access to the final
dataset. Of the multiple analyses done during the study, relevant co-investigators for
each analysis (e.g. RNAseq for Cate Speake) will have access to the datasets they have
contributed to.
Public and Patient Involvement The CI's direct contact with patients with a diagnosis of
diabetes in the first 12 months of life led to the study design. Patients, relatives and
clinicians agree there would be significant benefit to knowing why and how T1D can
present so young and whether understanding this could help with treatment or prevention.
Funders: Diabetes UK; The Leona M. and Harry B. Helmsley Charitable Trust. Publication
Policy: On completion of the study, the data will be analysed and a Final Study Report
will be prepared and submitted to the Funders, Sponsor and REC.